Discovery of Novel, Potent N-methyl-D-aspartate receptor Positive Allosteric Modulators (PAMs) with Antidepressant-like Activity in rodent models
Discovery of Novel, Potent N-methyl-D-aspartate receptor Positive Allosteric Modulators (PAMs) with Antidepressant-like Activity in rodent models
复制标题
在啮齿动物模型中发现具有抗抑郁样活性的新型强效 N-甲基-D-天冬氨酸受体正变构调节剂 (PAM)
DOI：
10.1021/acs.jmedchem.0c02018
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发表时间：
2021
影响因子：
7.3
通讯作者：
Liangren Zhang
中科院分区：
文献类型：
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作者：
Zhongtang Li;Guanxing Cai;Fan Fang;Wenchao Li;Minghua Fan;Jingjing Lian;Yilin Qiu;Xiangqing Xu;Xuehui Lv;Yiyan Li;Ruqiu Zheng;Yuxi Wang;Zhongjun Li;Guisen Zhang;Zhenming Liu;Zhuo Huang;Liangren Zhang
N-甲基-d-天冬氨酸受体（NMDAR）是谷氨酸门控的Na+和Ca 2+渗透性离子通道，参与兴奋性突触传递和突触可塑性。NMDAR功能低下长期以来一直与包括重度抑郁症（MDDs）在内的病理生理学有关。在此，我们报告了一系列呋喃-2-甲酰胺类似物作为新的NMDAR阳性变构调节剂（PAM）。通过基于结构的虚拟筛选和电生理测试，FS 2921被鉴定为具有潜在抗抑郁作用的新型NMDAR PAM。进一步的结构-活性关系研究导致发现了具有增强作用的新型类似物。化合物32 h在体外引起NMDAR兴奋性的显著增加，并且在强迫游泳试验中引起令人印象深刻的活性。此外，化合物32 h未显示出对hERG或细胞活力的显著抑制，并且具有有利的PK/PD特征。我们的研究提供了一系列新的NMDAR PAM，并为发现新的抗抑郁药提供了潜在的机会。
N-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na+and Ca2+-permeable ion channels involved in excitatory synaptic transmission and synaptic plasticity. NMDAR hypofunction has long been implicated in the pathophysiology including major depressive disorders (MDDs). Herein, we report a series of furan-2-carboxamide analogues as novel NMDAR-positive allosteric modulators (PAMs). Through structure-based virtual screen and electrophysiological tests, FS2921 was identified as a novel NMDAR PAM with potential antidepressant effects. Further structure–activity relationship studies led to the discovery of novel analogues with increased potentiation. Compound32hcaused a significant increase in NMDAR excitabilityin vitroand impressive activity in the forced swimming test. Moreover, compound32hshowed no significant inhibition of hERG or cell viability and possessed a favorable PK/PD profile. Our study presented a series of novel NMDAR PAMs and provided potential opportunities for discovering of new antidepressants.